A Drug to Gain Fat?

Jan. 27, 2006

Hope of Treatments Beyond Facial Fillers

There is currently no cure for lipoatrophy. Even the so-called "treatments," such as poly-L-lactic acid (Sculptra, New-Fill), Radiesse (calcium hydroxylapatite, Radiance), polydimethylsiloxane (Silikon 1000) and poly-Alkyl-Imide (Bio-Alcamid), are facial fillers that can correct the symptoms of lipoatrophy wonderfully well but leave the actual problem -- fat-cell destruction -- untouched (see Lipo Fixes).

Fortunately, it's now known that certain HIV meds are the cause, and by switching off of nucleoside reverse transcriptase inhibitors (NRTIs, also known as nukes), such as d4T (stavudine, Zerit), AZT (zidovudine, Retrovir) and ddI (didanosine, Videx), to more lipo-friendly drugs, such as tenofovir (Viread) or abacavir (Ziagen), you can arrest the process. But can you ever recover that lost layer of fat in your face, arms and legs, or butt? Kinda, sorta, maybe.

Most researchers agree that lipoatrophy is "reversible, but ..." When fat cells return, they do so only extremely slowly, over a period of years, and even then, only partially. The prospect of living with cadaverous cheeks and AIDS stigma for the rest of their lives has HIVers who cannot afford the facial-filler treatments eager for news of drugs that might hurry up the recovery.

We asked a leading lipo expert, Kathleen Mulligan, Ph.D., a professor and researcher at the University of California at San Francisco School of Medicine, for an update. Mulligan has been working with HIVers since the early '90s. Back then, her focus was AIDS wasting, which is a major metabolic and nutritional complication of HIV that causes severe fat and muscle loss in people with a low CD4 count in the throes of late-stage disease.

She quickly shifted gears in the late '90s, when weird fat disorders -- originally misidentified as the fat-redistribution syndrome dubbed lipodystrophy and now recognized as several separate and distinct problems, including lipoatrophy's fat loss -- began making healthy HIVers lives so difficult. According to Mulligan, the research is not exactly going gangbusters. There are two main drugs under investigation, and neither has Mulligan and other researchers kicking up their heels.

Uridine

What It Is: A naturally occurring nucleoside molecule central to the functioning of mitochondria. It is available commercially in a dietary supplement called NucleomaxX that contains Mitocnol, a sugar-cane extract rich in nucleosides.

Most researchers agree that lipoatrophy is "reversible, but ..." When fat cells return, they do so only extremely slowly, over a period of years, and even then, only partially.

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How It Works: In studies, adding uridine helped protect fat cells from the nasty effects of d4T, AZT and other lipoatrophy-related nukes.

"The rationale behind using uridine is that one side effect of mitochondrial damage might be a reduction in nucleoside production," Mulligan says, "and by giving uridine, which is a nucleoside, you're overcoming that deficiency, and by overcoming this deficiency, perhaps you could reverse some of the lipoatrophic effects of the nucleosides." That's the theory. But does it work?

How It Tested: Only one small study has been done well, and it showed that the 10 HIVers on NucleomaxX did in fact have an increase in fat in their limbs and belly (facial lipoatrophy was not measured). The amount of recovered fat, however, was somewhat underwhelming -- a little over a pound after three months, which, as Mulligan helpfully but messily describes, is about four sticks of butter spread out over your limbs and belly.

Plus, it remains to be seen whether uridine specifically helps reverse the loss of subcutaneous fat by kick-starting the mitochondria or more generally helps stimulate the body's production of all fat by some other mechanism.

Still, four sticks of butter worth of fat is the three-month record in lipoatrophy studies -- it's more than the amount of fat regained by HIVers who simply switched off the offending nukes or those who have tried the anti-lipo glitazone drugs.

The Take Home: "Before I ran out and spent money on it, I would want to see more data," Mulligan says. Still, there are numerous anecdotal reports of HIVers who swear by NucleomaxX.

Glitazones

What They Are: A class of drugs approved to reverse insulin resistance related to type 2 diabetes. In studies, troglitazone, the first in the class, looked like a possible homerun for both lipoatrophy and lipohypertrophy because diabetics who took the drug not only gained subcutaneous fat in their limbs but lost visceral fat in their bellies. Unfortunately, a few also developed life-threatening liver problems, so the drug was yanked from the market. Its two offspring, pioglitazone (Actos) and rosiglitazone (Avandia), although much safer, "don't have the same dramatic effects on visceral and subcutaneous [fat]," Mulligan says.

How They Work: The glitazone drugs stimulate the body's production of PPAR-gamma, a protein used in the creation of fat cells and in maintaining cell sensitivity to insulin. In studies, adding pioglitazone or rosiglitazone helped protect fat cells from the nasty effects of HIV meds associated with both lipoatrophy and lipohypertrophy -- by a complex mechanism different from that of uridine, one not directly related to mitochondrial toxicity.

How They Tested: The biggest rosiglitazone study was dubbed ROSEY, although the results were anything but. The drug showed "no positive effect on subcutaneous fat in people with HIV lipoatrophy," says Mulligan, cautioning that a closer look at the data suggests that a certain subgroup of patients on the drug did up their quota of subcutaneous fat.

More recently, smaller studies of both rosiglitazone and pioglitazone tend to confirm this more hopeful finding. "But the people most likely to benefit are those who are [or were] not taking d4T, and that's unfortunate, because those are probably the people who need it most," Mulligan says.

The Take Home: In "sticks of butter" effects, the best the glitazones have been able to accomplish is about three in a year (three quarters of a pound), while a big study of people who simply switched from d4T or AZT to the nuke abacavir got all the way to nine sticks of butter (two and a quarter pounds of subcutaneous fat) after two years. Still, Mulligan says that more research may clarify to what extent glitazones help accelerate fat-loss reversal in certain post-switch lipo-sufferers.

Uridine and the glitazones are the only treatments that have been earnestly researched for lipoatrophy. But many HIVers have, over the years, experimented with dietary supplements, including L-carnitine and coenzyme Q10, both of which may have some effect on mitochondrial health, as well as C and B-complex vitamins. In the general absence of a demand for more research, the supply of studies into drugs to cure or speed the reversal of lipoatrophy is likely to remain a little disappointing.

All that may change in about a decade, however. With access to HIV treatment in the developing world steadily improving, and with generic d4T, which is effective, cheap and easy to make, ever more widely prescribed, a million-plus HIVers may soon be walking around with puppet face, stick legs and arms and other markers of AIDS. No matter how grateful they are to be alive and healthy, losing their face and the self-esteem and sense of identity associated with that will be a very bitter pill to swallow. A global movement for a drug to gain fat may not be far off.